Herein we report the design, synthesis, X-ray structural, and biological studies of an exceptionally potent HIV-1 protease inhibitor, compound 5 ((3S,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl ((2S,3R)-4-((2-(cyclopropylamino)-N-isobutylbenzo[d]thiazole)-6-sulfonamido)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)carbamate). Using structure-based design, we incorporated an unprecedented 6-5-5-ring-fused crown-like tetrahydropyranofuran as the P2-ligand, a cyclopropylaminobenzothiazole as the P2'-ligand, and a 3,5-difluorophenylmethyl group as the P1-ligand. The resulting inhibitor 5 exhibited exceptional HIV-1 protease inhibitory and antiviral potency at the picomolar level. Furthermore, it displayed antiviral IC50 values in the picomolar range against a wide panel of highly multidrug-resistant HIV-1 variants. The inhibitor shows an extremely high genetic barrier against the emergence of drug-resistant variants. It also showed extremely potent inhibitory activity toward dimerization as well as favorable central nervous system penetration. We determined a high-resolution X-ray crystal structure of the complex between inhibitor 5 and HIV-1 protease, which provides molecular insight into the unprecedented activity profiles observed.

中文翻译：

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高效、双重作用和穿透中枢神经系统的 HIV-1 蛋白酶抑制剂的设计，对多药耐药 HIV-1 变体具有出色的效力。

在此我们报告了一种特别有效的 HIV-1 蛋白酶抑制剂化合物 5 ((3S,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3] 的设计、合成、X 射线结构和生物学研究-b]吡喃-8-基((2S,3R)-4-((2-(环丙基氨基)-N-异丁基苯并[d]噻唑)-6-磺酰氨基)-1-(3,5-二氟苯基)-3 -羟基丁-2-基)氨基甲酸酯)。使用基于结构的设计，我们结合了前所未有的 6-5-5-环稠合冠状四氢吡喃呋喃作为 P2-配体，环丙基氨基苯并噻唑作为 P2'-配体，以及 3,5-二氟苯基甲基作为 P1-配体。由此产生的抑制剂 5 在皮摩尔水平上表现出卓越的 HIV-1 蛋白酶抑制和抗病毒效力。此外，它还显示了针对大量高度多重耐药 HIV-1 变体的皮摩尔范围内的抗病毒 IC50 值。该抑制剂对耐药变体的出现显示出极高的遗传屏障。它还显示出对二聚化的极强抑制活性以及有利的中枢神经系统渗透。我们确定了抑制剂 5 和 HIV-1 蛋白酶之间复合物的高分辨率 X 射线晶体结构，这为观察到的前所未有的活性概况提供了分子洞察力。